Prostate cancer accounts for 33% of all newly diagnosed malignancies among men in the United States (American Cancer Society: Cancer Facts and Figures (2003)). According to the American Cancer Society, an estimated 230,110 men will be diagnosed with prostate cancer in 2004, and 29,900 men will die of it (American Cancer Society: Cancer Facts and Figures (2004)). The incidence of prostate cancer varies worldwide, with the highest rates found in the United States, Canada, and Scandinavia, and the lowest rates found in China and other parts of Asia (Quinn and Babb, “Patterns and Trends in Prostate Cancer Incidence, Survival, Prevalence and Mortality. Part: International Comparisons,” BJU Int. 90:162-173 (2002); Gronberg, “Prostate Cancer Epidemiology,” Lancet 361:859-864 (2003)). These differences are caused by genetic susceptibility, exposure to unknown external risk factors, differences in health care and cancer registration, or a combination of these factors.
Cancer of the prostate is multifocal and it is commonly observed that the cancerous gland contains multiple independent lesions, suggesting the heterogeneity of the disease (Foster et al., “Cellular and Molecular Pathology of Prostate Cancer Precursors,” Scand. J. Urol. Nephrol. 205:19-43 (2000)). Determinants responsible for the pathologic growth of the prostate remain poorly understood, although steroidal androgens and peptide growth factors have been implicated (Agus et al., “Prostate Cancer Cell Cycle Regulators: Response to Androgen Withdrawal and Development of Androgen Independence,” J. Natl. Cancer. Inst. 91:1869-1876 (1999); Djakiew, “Dysregulated Expression of Growth Factors and Their Receptors in the Development of Prostate Cancer,” Prostate 42:150-160 (2000)). As long as the cancer is confined to the prostate, it can be successfully controlled by surgery or radiation, but in metastatic disease, few options are available beyond androgen ablation (Frydenberg et al., “Prostate Cancer Diagnosis and Management,” Lancet 349:1681-1687 (1997)), the mainstay of treatment in the case of lymph node involvement or disseminated loci. Once tumor cells have become hormone refractory, the standard cytotoxic agents are marginally effective in slowing disease progression, although they do provide some degree of palliative relief. Current chemotherapeutic regimens, typically two or more agents, afford response rates in the range of only 20-30% (Beedassy et al., “Chemotherapy in Advanced Prostate Cancer,” Sem. Oncol. 26:428-438 (1999); Raghavan et al., “Evolving Strategies of Cytotoxic Chemotherapy for Advanced Prostate Cancer,” Eur. J. Cancer 33:566-574 (1997)).
One promising drug development strategy for prostate cancer involves identifying and testing agents that interfere with growth factors and other molecules involved in the cancer cell's signaling pathways. G-protein coupled receptors (“GPCRs”) are a family of membrane-bound proteins that are involved in the proliferation and survival of prostate cancer cells initiated by binding of lysophospholipids (“LPLs”) (Raj et al., “Guanosine Phosphate Binding Protein Coupled Receptors in Prostate Cancer: A Review,” J. Urol. 167:1458-1463 (2002); Kue et al., “Essential Role for G Proteins in Prostate Cancer Cell Growth and Signaling,” J. Urol. 164:2162-2167 (2000); Guo et al., “Mitogenic Signaling in Androgen Sensitive and Insensitive Prostate Cancer Cell Lines,” J. Urol. 163:1027-1032 (2000); Barki-Harrington et al., “Bradykinin Induced Mitogenesis of Androgen Independent Prostate Cancer Cells,” J. Urol. 165:2121-2125 (2001)). The importance of G protein-dependent pathways in the regulation of growth and metastasis in vivo is corroborated by the observation that the growth of androgen-independent prostate cancer cells in mice is attenuated by treatment with pertussis toxin, an inhibitor of Gi/o proteins (Bex et al., “Influence of Pertussis Toxin on Local Progression and Metastasis After Orthotopic Implantation of the Human Prostate Cancer Cell Line PC3 in Nude Mice,” Prostate Cancer Prostatic Dis. 2:36-40 (1999)). Lysophosphatidic acid (“LPA”) and sphingosine 1-phosphate (“S1P”) are lipid mediators generated via the regulated breakdown of membrane phospholipids that are known to stimulate GPCR-signaling.
LPL binds to GPCRs encoded by the Edg gene family, collectively referred to as LPL receptors, to exert diverse biological effects. LPA stimulates phospholipase D activity and PC-3 prostate cell proliferation (Qi et al., “Lysophosphatidic Acid Stimulates Phospholipase D Activity and Cell Proliferation in PC-3 Human Prostate Cancer Cells,” J. Cell. Physiol. 174:261-272 (1998)). Further, prior studies have shown that LPA is mitogenic in prostate cancer cells and that PC-3 and DU-145 express LPA1, LPA2, and LPA3 receptors (Daaka, “Mitogenic Action of LPA in Prostate,” Biochim. Biophys. Acta. 1582:265-269 (2002)). Advanced prostate cancers express LPL receptors and depend on phosphatidylinositol 3-kinase (“PI3K”) signaling for growth and progression to androgen independence (Kue and Daaka, “Essential Role for G Proteins in Prostate Cancer Cell Growth and Signaling,” J. Urol. 164:2162-2167 (2000)). Thus, these pathways are widely viewed as one of the most promising new approaches to cancer therapy (Vivanco et al., “The Phosphatidylinositol 3-Kinase AKT Pathway in Human Cancer,” Nat. Rev. Cancer 2:489-501 (2002)) and provide an especially novel approach to the treatment of advanced, androgen-refractory prostate cancer. Despite the promise of this approach, there are no clinically available therapies that selectively exploit or inhibit LPA or PI3K signaling.
Melanoma is the most aggressive form of skin cancer and is the fastest growing cancer currently in the United States (Ries et al., “The Annual Report to the Nation on the Status of Cancer, 1993-1997, with a Special Section on Colorectal Cancer,” Cancer 88:2398-2424 (2000); Jemal et al., “Recent Trends in Cutaneous Melanoma Incidence Among Whites in the United States,” Cancer Inst. 93:678-683 (2001); Jemal et al., “Cancer Statistics, 2004,” CA Cancer J. Clin. 54:8-29 (2004)). It is the most common cancer in young adults aged 20-30. Approximately two to three out of 100,000 people per year die from melanoma in the northern hemisphere (Marks, “Epidemiology in Melanoma,” Clin. Exp. Dermatol. 25:459-463 (2000); Lens et al., “Global Perspectives of Contemporary Epidemiological Trends of Cutaneous Malignant Melanoma,” Br. J. Dermatol. 150:179-185 (2004)). While in situ melanoma (stage 0) can usually be cured surgically, melanoma metastized to major organs (stage IV) is virtually incurable. Patients with advanced melanoma have median survival time of 7.5 months and the estimated five year survival rate is only 5-9% (Barth et al., “Prognostic Factors in 1,521 Melanoma Patients with Distant Metastases,” J. Am. Coll. Surg. 181:193-201 (1995); Buzaid et al., “The Changing Prognosis of Melanoma,” Curr. Oncol. Rep.2:322-328 (2000); Anderson et al., “Systemic Treatments for Advanced Cutaneous Melanoma,” Oncology (Williston Park) 9:1149-1158, discussion 1163-1144, 1167-1148 (1995)).
Currently, dacarbazine (“DTIC”) is the only U.S. Food and Drug Administration (“FDA”) approved drug to treat advanced melanoma, and it provides complete remission in only two percent of patients (Anderson et al., “Systemic Treatments for Advanced Cutaneous Melanoma,” Oncology (Williston Park) 9:1149-1158, discussion 1163-1144, 1167-1148 (1995); Serrone et al., Dacarbazine-based Chemotherapy for Metastatic Melanoma: Thirty-year Experience Overview,” J. Exp. Clin. Cancer Res. 19:21-34 (2000)). The FDA also approved the use of high-dose interferon alpha-2b (“IFN-α2b”) as adjuvant treatment of patients at high risk of recurrence of melanoma, but a total of four recent Phase III randomized trials failed to detect a survival advantage with the addition of IFN-α2b to DTIC (Lawson, “Choices in Adjuvant Therapy of Melanoma,” Cancer Control 12:236-241 (2005); Bajetta et al., “Multiicenter Randomized Trial of Dacarbazine Alone or in Combination with Two Different Doses and Schedules of Interferon alpha-2a in the Treatment of Advanced Melanoma,” J. Clin. Oncol. 12:806-811 (1994); Thomson et al., “Interferon alpha-2a Does Not Improve Response or Survival when Combined with Dacarbazine in Metastatic Malignant Melanoma: Results of a Multi-institutional Australian Randomized Trial,” Melanoma Res. 3:133-138 (1993); Young et al., “Prospective Randomized Comparison of Dacarbazine (DTIC) Versus DTIC Plus Interferon-alpha (IFN-alpha) in Metastatic Melanoma,” Clin. Oncol. (R. Coll. Radiol) 13:458-465 (2001)). Several extensive clinical trials have been conducted in recent years with a variety of cancer drugs or combination of cancer drugs, but thay all failed to demonstrate clear effect against advanced melanoma (Lawson, “Choices in Adjuvant Therapy of Melanoma,” Cancer Control 12:236-241 (2005); Mandara et al., “Chemotherapy for Metastatic Melanoma,” Exp. Rev. Anticancer Ther. 6:121-130 (2006); Kaufmann et al., “Temozolomide in Combination with Interferon-alpha Versus Temozolomide Alone in Patients with Advanced Metastatic Melanoma: A Randomized, Phase III, Multicenter Study from the Dermatologic Cooperative Oncology Group,” J. Clin. Oncol. 23(25):9001-9007 (2005)). Therefore, DTIC still remains the gold standard for advanced melanoma despite its very limited efficacy (Eggermont et al., “Re-evaluating the role of Dacarbazine in Metastatic Melanoma: What Have We Learned in 30 Years?” Eur. J. Cancer 40:1825-1836 (2004); Atallah et al., “Treatment of Metastatic Malignant Melanoma,” Curr. Treat Options Oncol. 6:185-193 (2005)). With the rapidly rising incidents reported for melanoma in the United States, clearly there is an urgent need to develop more effective therapeutic agents to combat advanced melanoma.
The present invention is directed to overcoming these and other deficiencies in the prior art.